3-Nitro-naphthalimide and nitrogen mustard conjugate NNM-25 induces hepatocellular carcinoma apoptosis via PARP-1/p53 pathway

Hepatocellular carcinoma (HCC) is one of the main causes of death in cancer. Some naphthalimide derivatives exert high anti-proliferative effects on HCC. In this study, it is confirmed that 3-nitro-naphthalimide and nitrogen mustard conjugate (NNM-25), a novel compound conjugated by NNM-25, displayed more potent therapeutic action on HCC, both in vivo and in vitro, than amonafide, a naphthalimide drug in clinical trials. More importantly, preliminary toxicological evaluation also supported that NNM-25 exhibited less systemic toxicity than amonafide at the therapeutic dose. The antitumor mechanism of conjugates of naphthalimides with nitrogen mustard remains poorly understood up to now. Here, we first reported that apoptosis might be the terminal fate of cancer cells treated with NNM-25. Inhibition of p53 by siRNA resulted in a significant decrease of NNM-25-induced apoptosis, which corroborated that p53 played a vital role in the cell apoptosis triggered by NNM-25. NNM-25 inhibited the PARP-1 activity, AKT phosphorylation, up-regulated the protein expression of p53, Bad, and mTOR as well as down-regulating the protein expression of Bcl-2 and decreasing mitochondrial membrane potential. It also facilitated cytochrome c release from mitochondria to cytoplasm, activated caspase 8, caspase 9, and caspase 3 in HepG2 cells in vitro, as also authenticated in H22 tumor-bearing mice in vivo. Collectively, the conjugation of naphthalimides with nitrogen mustard provides favorable biological activity and thus is a valuable strategy for future drug design in HCC therapy.     

Suppressed recombination rate in 6VS/6AL translocation region carrying the Pm21 locus introgressed from Haynaldia villosa into hexaploid wheat

Pm21 is an effective gene for powdery mildew resistance transferred from Haynaldia villosa into common wheat cultivars. No virulence against this gene has been detected so far. A set of 42 powdery mildew isolates collected in Israel and tested in the current study also revealed no virulence against this gene. Pm21 was previously reported to be located on the short arm of 6VS/6AL translocation chromosome. We constructed a high-density genetic map of chromosome 6A, consisting of 28 PCR markers and the Pm21 gene. A comparison with previously published genetic maps of wheat chromosome 6A revealed that the recombination rate in the 6VS/6AL translocation region was poor. We assume that suppressed recombination caused by the alien H. villosa genetic material is the most reasonable explanation for the tight genetic linkage and the inadequacy between the Pm21 genetic map and the Pm21 physical map of 6A. A large number of sequence-tag sites (STS) and simple sequence repeat markers, which co-segregate with or are closely linked to the Pm21 gene, and the conversion of three resistance gene analog markers into new STS markers, provide a reliable and easy-to-use molecular tool for marker-assisted selection of Pm21 in wheat breeding programs. An additional gene, Pm31, previously reported to be derived from Triticum dicoccoides, was mapped into a similar genomic location to Pm21. Screening of the parental lines and the mapping population with Pm21 diagnostic markers clearly confirmed that the donor line of Pm31 is H. villosa and not T. dicoccoides. Therefore, we conclude that Pm21 and Pm31 refer to the same gene, derived from H. villosa, and that the designation of Pm31 as a new Pm gene was erroneous.     

Canopy and leaf photosynthetic characteristics and water use efficiency of sweet sorghum under drought stress

The objective of this paper was to examine the relationship between Water Use Efficiency (WUE) at the canopy and leaf levels, to determine soil moisture conditions, which can optimize yield, and WUE of sweet sorghum (Sorghum bicolor (Linn.) Moench), thus providing some theoretical foundation for using marginal land effectively and developing production of sweet sorghum. Three levels of soil moisture conditions were established, and photosynthetic characteristics and yield were measured. The canopy apparent photo-synthetic rate (CAP) and leaf photosynthetic rate (P _N) were reduced gradually with increased drought stress, and the CAP was lower than the P _N under every soil moisture conditions. The P _N had a midday depression phenomenon, but the CAP did not exhibit this midday depression phenomenon under severe drought stress. The linear regression relationship of CAP and P _N was CAP = 1.5945 + 0.1496 P _N. The canopy apparent WUE_C and leaf WUE_L were the highest under moderate drought stress. The first was 5.3 and 5.8 times higher than the WUE_L in mid-July and late August, respectively. The stem fresh biomass yield was 77 tons/ha under moderate drought stress and WUE of aboveground biomass yield (WUE_B) was also the highest. Our results showed that moderate drought stress did not result in a significant reduction in biomass yield but increased WUE significantly.     

Polymorphisms of the myostatin gene and its relationship with reproduction traits in the bian chicken

Myostatin, or growth and differentiation factor 8, is a member of the transforming growth factor-β superfamily; it functions as a negative regulator of skeletal muscle development and growth in mammals. In this study, single nucleotide polymorphisms in the 5' regulatory region and exon 1 of the myostatin gene were detected by PCR-SSCP in the Bian, Jinghai, Youxi, and Arbor Acre chickens, and the associations of the polymorphisms with reproduction traits were analyzed. Seven SNPs (A326G, C334G, C1346T, G1375A, A1473G, G1491A, and G2283A) were found in the myostatin gene. Association analysis showed that the G2283A were significantly associated with reproduction traits. Bian chickens of the GG genotype had a greater age at first egg than those of the GA and AA genotypes (P?相似文献   

Importance of Arsenic Speciation in Populations Exposed to Arsenic in Drinking Water

Total arsenic in urine is often the principal means for assessing chronic exposure to arsenic-contaminated drinking water. This approach ignores many components of the human diet, especially fish and seafood that contain arsenic at significant concentrations. The toxicity differences between the inorganic forms and the dietary forms suggest both should be evaluated when attempting to assess risk from arsenic exposure. Urine biomonitoring for 53 participants was used to confirm reduction in arsenic exposure resulting from well water remediation removing inorganic arsenic from drinking water. Initially, only total arsenic urine assays were performed, but spikes in total arsenic urine concentrations were determined to be diet related and demonstrated the need for analytical methods that differentiate the arsenic species. A secondary analysis was added that quantified inorganic-related arsenic in urine and the dietary forms related to fish and seafood by subtraction from total arsenic. Significant differences were found between the inorganic arsenic component and the total arsenic measured in their urine. On average, approximately 76% of total arsenic in urine was attributed to fish and other organo-arsenic dietary sources, implying a potential significant overestimate of exposure, and demonstrating the need for differentiation of the inorganic-related arsenic from dietary arsenic.     

Electrophysiologic Characteristics of the Crista Terminalis and Implications on Atrial Tachycardia in Rabbits

The objective of this study was to evaluate the electrophysiologic characteristics of Crista terminalis (CT) and their implication in the pathogenesis of atrial tachycardia in rabbits. For this purpose, 27 New Zealand rabbits were used. Using standard glass microelectrode technique, cellular action potentials (APs) of CT and pectinate muscle (PM) were recorded in normal Tyrode’s perfusion and Tyrode’s perfusion with 4 μM isoproterenol. Longitudinal conduction velocity (V _L) and transverse conduction velocity (V _T) of CT were measured. As our data show, CT tissue had a trend of spontaneous phase IV depolarization. Conduction anisotropy (V _L/V _T) of CT was 4.53 ± 0.91. The duration of the AP of CT was longer than that of PM cells. APD₂₀ and APD₉₀ for CT were 28.1 ± 3.5 and 145.3 ± 7.1 ms; and for PM cells were 21.8 ± 4.1 and 125.3 ± 6.3 ms, respectively (all P values < 0.01). The early and delayed action depolarizations were recorded after isoproterenol perfusion. A fast paroxysmal irregular rhythm was recorded which could be arrested by 0.1 mmol/l Isoptin. It was, therefore, concluded that the latent autorhythmicity, trigger activity, and conduction properties of CT might provide the electrophysiologic basis for the occurrence and sustenance of atrial arrhythmia.     

Membrane mechanisms for signal transduction: the coupling of the meso-scale raft domains to membrane-skeleton-induced compartments and dynamic protein complexes

Virtually all biological membranes on earth share the basic structure of a two-dimensional liquid. Such universality and peculiarity are comparable to those of the double helical structure of DNA, strongly suggesting the possibility that the fundamental mechanisms for the various functions of the plasma membrane could essentially be understood by a set of simple organizing principles, developed during the course of evolution. As an initial effort toward the development of such understanding, in this review, we present the concept of the cooperative action of the hierarchical three-tiered meso-scale (2-300 nm) domains in the plasma membrane: (1) actin membrane-skeleton-induced compartments (40-300 nm), (2) raft domains (2-20 nm), and (3) dynamic protein complex domains (3-10nm). Special attention is paid to the concept of meso-scale domains, where both thermal fluctuations and weak cooperativity play critical roles, and the coupling of the raft domains to the membrane-skeleton-induced compartments as well as dynamic protein complexes. The three-tiered meso-domain architecture of the plasma membrane provides an excellent perspective for understanding the membrane mechanisms of signal transduction.     

Efficacy and Safety of Right Hemihepatectomy Through the Right Retrohepatic Tunnel

We wished to study the efficacy and safety of the retrograde ligation of short hepatic veins (SHVs) and the right hepatic vein (HV) through the retrohepatic tunnel in patients who underwent hemihepatectomy due to large hepatic carcinoma in the right lobe of the liver. Right hemihepatectomy was performed in 23 patients with tumors larger than 8 cm in diameter. The liver was separated at the secondary porta, and the interspace between right HVs and middle HVs was expanded. The right hepatic portal vein and hepatic artery were freed and ligated, followed by the retrograde dissection of SHVs and the right HV along the right retrohepatic space anterior to the inferior vena cava. A blocking belt was set at the left side of the midline, after which the right liver was cut off. The procedure was successfully completed in all patients. The average amount of intraoperative blood loss was 640 ml. The change in hepatic function was observed on the third postoperative day. Twenty-two patients exhibited satisfactory results; one patient died from postoperative hepatic failure. In conclusion, this procedure can be safely performed in most hemihepatectomy patients with liver tumors.